Project Summary Oxidation reactions exhibit significant value in the synthesis of pharmaceuticals, natural products and other bioactive compounds. The proposed studies will develop powerful new synthetic methods for selective oxidative functionalization of C(sp3)?H bonds. Benzylic C?H bonds represent a strategic target: such bonds are ubiquitous in pharmaceuticals and they are comparatively weak relative to most other C?H bonds. The latter feature provides the basis for selective functionalization of these sites via radical intermediates. In addition, benzylic sites often contribute to the metabolic instability of pharmaceuticals, and their selective modification will confer enhanced biological potency. Our efforts target the development of synthetic methods that may be readily adapted to pharmaceutical discovery and facilitate access to drug candidates with more-complex three dimensional architectures. The project will employ two complementary experimental strategies. One will make use of chemical oxidants that initiate selective hydrogen-atom abstraction from benzylic sites, while the second will exploit electrochemical methods that utilize catalytic electron-, electron/proton-, or hydrogen-atom-abstraction mediators to generate radical intermediates. Both the chemical and electrochemical methods will target benzylic C?H coupling reactions that generate diversely functionalized products. The electrochemical methodology will also target the generation of radicals that undergo addition reactions with (hetero)aromatic rings to produce medicinally relevant aromatic molecules. Several of the benzylic C?H oxidative coupling reactions show effective reactivity with the benzylic coupling partner as the limiting reaction, thereby making them highly appealing for late-stage functionalization of complex molecules. Opportunities toward this end will be explored in collaboration with Merck. Overall, the complementary chemical and electrochemical C?H oxidation methods are poised to greatly impact drug discovery efforts.